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Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2013 Jul 01; Vol. 19 (13), pp. 3681-92. Date of Electronic Publication: 2013 May 17. - Publication Year :
- 2013
-
Abstract
- Purpose: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients.<br />Experimental Design: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF-dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF)-containing therapy.<br />Results: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies.<br />Conclusions: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials.<br /> (©2013 AACR.)
- Subjects :
- Angiogenesis Inhibitors pharmacology
Animals
Antibodies, Monoclonal, Humanized pharmacology
Antibodies, Monoclonal, Humanized therapeutic use
Antineoplastic Agents pharmacology
Bevacizumab
Biomarkers, Tumor genetics
Biomarkers, Tumor metabolism
Disease Models, Animal
Drug Evaluation, Preclinical
Gene Expression Profiling
Gene Expression Regulation, Neoplastic drug effects
Humans
Mice
Neoplasms genetics
Neoplasms mortality
Neovascularization, Pathologic drug therapy
Neovascularization, Pathologic genetics
Neovascularization, Pathologic metabolism
Neuroendocrine Tumors drug therapy
Neuroendocrine Tumors genetics
Neuroendocrine Tumors metabolism
Pancreatic Neoplasms drug therapy
Pancreatic Neoplasms genetics
Pancreatic Neoplasms metabolism
Angiogenesis Inhibitors therapeutic use
Antineoplastic Agents therapeutic use
Neoplasms drug therapy
Neoplasms metabolism
Signal Transduction drug effects
Vascular Endothelial Growth Factor A antagonists & inhibitors
Vascular Endothelial Growth Factor A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 19
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 23685835
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-12-3635